Why can’t I have children?

A lot of couples cannot have children. So, it is calculated that more than 48 million couples in the world are infertile. The mother’s age in the first gestation is important, but many times it is due by a genetic problem. Infertility is a clear example of complex disease with genetics base. The following is an explanation of genetic base of infertility in men and women.

INFERTILITY OR STERILITY?

You can think that infertility and sterility are synonymous, but they do not mean the same (Figure 1). However, infertility is the Anglo-Saxon word and the most used.

According to WHO, sterility is the difficulty getting a pregnancy after 1 year of frequent sexual relations near ovulation’s day and without protection. There are primary sterility and secondary sterility.

We talk to primary sterility when a woman is unable to become pregnant, while secondary sterility is when a woman in unable to become pregnant after having pregnancy history.

Infertility is when there is fecundation, but there are not implantation or an abort. There are primary infertility and secondary infertility too.

When a woman is unable to ever bear a child, due to the inability to carry a pregnancy to a live birth she would be classified as having primary infertility. However, when a woman is unable to carry a pregnancy to a live birth following either a previous pregnancy or a previous ability to carry a pregnancy to a live birth, she would be classified as having secondary infertility. Thus, women will suffer repetitive spontaneous miscarriages.

Figure 1. Schematic drawing of the difference between infertility and infertility (Source: Reproducción Asistida ORG, modified)

SOME INTERESTING FACTS

It is important to know that suffer a spontaneous aborts is normal in the reproductive history of a woman. It is estimated that 7 of 10 girls will suffer an abort during the first trimester.

Human species has not a high reproductive power, it is considered 25% the possibility of pregnancy in a sexual relation during the woman’s ovulation.

In addition, reproductive potential decreases when women are 35 years old. It is known that as of this age the reproductive potential drops and that after 40 years of age the possibility of pregnancy per month is less than 10%.

Approximately 1 of 6 couples in childbearing age is affected by sterility. This number represents 15-17% population.

GENETIC BASE OF MALE INFERTILITY

In men, up to 30% of infertility is associated with a direct genetic cause. A 50% of cases is indirect cause because the man is not just infertile, but he has other alterations and for this reason it is not classified like genetic anomaly. The remaining 20% has idiopathic origin, it means that is unknown cause (Figure 2).

Figure 2. Graphic showing the percentages of infertility’s causes (Source: Mireia Ramos, All You Need is Biology)

There are three types of genetics causes:

• Pre-testicular
• Testicular
• Post-testicular

PRE-TESTICULAR GENETIC CAUSES

These causes are associated before and during testicles developing:

• Alterations in testosterone synthesis.
• Alterations of the receptors of the hormones LH and FSH.
• Androgenic resistance syndromes: there is testicular feminization, it means the karyotype is masculine (46, XY), but the phenotype is feminine.
• Hypogonadism: testosterone deficiency with signs or symptoms associated, deficiency in sperm production or both. It could be because testicles are not functional or the affectation of hypothalamic-pituitary axis.

TESTICULAR GENETIC CAUSES

• Chromosomopathies: chromosomal abnormalities such as aneuploidies (abnormal number of chromosomes), chromosomal translocations (rearrangement of parts between nonhomologous chromosomes), inversions (a segment of a chromosome is reversed end to end) or trisomies.
• Meiotic abnormalities: abnormalities in germline .
• Microdeletions Yq: deletions of Y chromosome.
• Monogenic alterations: affecting a single gene.
• Gonadal dysgenesis: disorder of sexual development associated with anomalies in gonadal development, however having a male karyotype (46, XY), the external and internal genitalia are female.

POST-TESTICULAR GENETIC CAUSES

• Agenesis of vas deferens: absence of vas deferens, characteristic in cystic fibrosis.
• Sperm alterations.
• Autosomal dominant polycystic kidney: inherited disorder in which cysts form in the liver, pancreas and testes.

GENETIC BASE OF FEMALE INFERTILITY

Gene regulation of the formation and development of female sex cells (oogenesis) and ovarian follicle (folliculogenesis) is unmanageable and, in many cases, it is impossible to tell what the cause of infertility is.

Oocytes (female sex cells) need a suitable environment to grow and develop. The ovarian follicles surround the oocytes to provide them with this environment.

Even so, more or less we move with the same numbers as in men (Figure 2). 30% is for direct cause, where the genetic abnormality is known; 50% is due to indirect causes such as problems in the formation of hormones, and up to 20% for unknown reasons.

The genetic causes are divided into:

• Hypothalamic – pituitary axis
• Ovaries
• Uterine

GENETIC CAUSES RELATED TO HYPOTHALAMIC-PITUITARY AXIS

Endocrine system is formed by a series of glands that release the hormones. In this system, hypothalamic-pituitary axis is very important (Figure 3).

Figure 3. Hypothalamus-pituitary axis in detail, where you can see brain hemispheres (A), hypothalamus (B), pituitary (C), cerebellum (D) and brainstem (E) (Source: Sistema Endocrino, modified)

The pituitary gland is a small gland less than 1cm in diameter. This gland is attached to the hypothalamus, which controls almost all of its secretion. The hypothalamus is at the base of the brain and is the receiving center for signals from many areas of the brain, as well as internal organs, so that painful or stressful emotional experiences cause changes in your attitude. Likewise, the hypothalamus controls the autonomic nervous system and regulates body temperature, hunger, thirst, sexual behavior and defensive reactions, such as fear or rage.

The hypothalamic-pituitary axis regulates virtually all aspects of the body’s growth, development, metabolism and homeostasis.

The genetic causes of infertility related to this axis may have:

• Hypothalamic origin: problems with the development of the gonads.
• Hypophyseal origin: hormones.

OVARIAN GENETIC CAUSES

They are related to the ovaries and follicles. Chromosomal abnormalities are very important, especially those affecting the X chromosome.

UTERINE GENETIC CAUSES

They are related to the development of the endometrium, implantation of the embryo … The affectation of these phenomena implies infertility.

REFERENCES

• Foresta, C. et al. (2002). Guidelines for the appropriate use of genetic tests in infertile couples. Eur J Hum Genet; 10:303-312
• Hwang, K. et al.(2010). Mendelian genetics of male infertility. Ann N Y Acad Sci; 1214: E1-E17
• World Health Organization
• Reproducción Asistida ORG
• InfermeraVirtual
• El Mundo
• Main picture: Mujer Bien

Metamorphosis and amphibian larvae

The word amphibian comes from ancient Greek words “amphi”, which means “both” and “bios”, which means “life”. Even if the word amphibious is an adjective used to describe animals that can live both on land and water, in the case of amphibians it also refers to both life stages through which these animals go through, as amphibians are born in an aquatic larval stage and become adults via a process of metamorphosis. In this new entry we’ll explain how metamorphosis works at a hormonal level, which anatomical changes occur during this period and the differences of this process among the different lissamphibian orders.

LISSAMPHIBIAN METAMORPHOSIS

Metamorphosis is present in the three lissamphibian orders. This process was already present in the first terrestrial tetrapods, which had to lay their eggs in water. Yet not all extant species present external metamorphosis, as some of them hatch as diminutive adults (as 20% of anuran species). In these species metamorphosis happens equally inside the egg before hatching, what’s called internal metamorphosis.

Red-eyed tree frog eggs (Agalychnis callydryas) just before hatching, by Geoff Gallice.

As a general rule, lissamphibians lay their eggs in water. In most species, aquatic larvae will hatch from gelatinous eggs, even if their morphology varies a lot between different species. Yet larvae of all lissamphibians present a set of common characteristics:

• External gills, thanks to which they can breathe underwater.
• Absence of eyelids and retinal pigments associated with sight outside of water.
• Presence of a lateral line (or equivalent), sensorial organ characteristic of fish which allow them to sense vibrations underwater.
• Thinner skin.
• Subaquatic anatomic adaptations.

Photo of a fire salamander (Salamandra salamandra) in which the external gills and the pisciform looks of the larva can be appreciated, by David López.

During metamorphosis, most structures useful during the larval stage are reabsorbed through apoptosis, a controlled cell death process. In many cases this process is highly conditioned by various environmental factors such as population density, food availability and the presence of certain chemical substances in water.

HORMONAL CHANGES

At the hormonal level, metamorphosis is characterized by the interaction between two kinds of hormones: thyroid hormones and prolactin. While the thyroid hormones as thyroxin (secreted by the thyroid gland) stimulate the metamorphosis process, prolactin (secreted by the pituitary gland or hypophysis) inhibits it. The concentration of these two hormones (regulated by the Hypothalamus→Hyphophysis→Thyroid) is what controls the different stages of metamorphosis.

Scheme by Mikael Häggström of the hypothalamus (green), hypophysis or pituitary (red), thyroid (blue) axis in human beings and the release of thyroid hormones.

PREMETAMORPHOSIS

This is the larval growth stage, and it lasts around the first 20 days of life (depending on the species). This stage is characterized by a low secretion of thyroidal hormones and by a high concentration of prolactin that inhibits the metamorphosis process. This is due to the fact that the hypothalamus→hypophysis system is still not mature.

PROMETAMORPHOSIS

It’s a period of reduced growth with slow morphological changes, due to the rise of thyroxin concentration in blood caused by the growth of the thyroid gland. Also, the hypothalamus→hypophysis axis starts developing, which will trigger even more the rise of the thyroxin concentration and will lower the prolactin, giving way to great morphological changes.

METAMORPHOSIS CLIMAX

It’s the point in which the hyothalamus→hypophysis→thyroid axis is at its maximum capacity and it is when great morphological changes happen in the larva, which will end up becoming a miniature adult. Finally, thyroxin levels will start to be restored by a negative feedback system of the thyroxin over the hypothalamus and the hypophysis.

Scheme from Brown & Cai 2007, about the general levels of thyroid hormones during the different metamorphosis’ stages.

MORPHOLOGICAL CHANGES

During the metamorphosis process, larvae will go through a set of anatomical changes that will allow them to acquire their adult form. Some changes common to most species are the acquisition of eyelids and new retinal pigments, the reabsorption of the gills and the loss of the lateral line. Other morphological changes vary among the different orders. For example in caecilians (order Apoda) larvae already look like miniature adults but with external gills. Also, most caecilians present internal metamorphosis and the hatchlings have no trace of gills.

Photo from Blog do Nurof-UFC of a caecilian egg, inside which we can see the larva with gills.

In urodeles (order Urodela), the external metamorphic changes aren’t that spectacular either. Larvae are pretty similar to adults, as their limbs develop quickly, although they present external filamentous gills, have no eyelids and present a largely-developed caudal fin. Even their carnivorous diet is similar to that of the adult’s. Yet the great diversity of salamanders and newts gives as a result a great variety of life cycles; from viviparous species that give live birth, to neotenic species that keep larval characteristics through their adult stage.

Photo by David Alvarez of the viviparous birth of a fire salamander (Salamandra salamandra), and photo by Faldrian of an axolotl (Ambystoma mexicanum) a neotenic species.

Frogs and toads (order Anura) are the group in which metamorphic changes are more dramatic. The anuran larva is so different that it’s called a tadpole, which differentiates from the adult both by its looks and its physiology and behaviour. Even if tadpoles are born with external gills, these are soon covered by skin folds that form a gill chamber. Also, tadpoles have a round, limbless body and a long, vertically-flattened tail, which allows them to swim swiftly in water.

Photo by J. J. Harrison of a southern brown tree frog tadpole (Litoria ewingii).

One of the main differences between adult and larval anurans is their diet. While adult frogs and toads are predators, tadpoles are herbivorous larvae, feeding by filtering suspended vegetal particles or by scraping off algae from rocks using a series of keratinous “teeth” present in some species. This is reflected in their spirally-shaped and extremely long digestive system in order to allow them to digest large quantities of vegetal matter. Tadpoles are tireless eating machines, with some filter-feeding species being able to filter eight times their body volume of water per minute.

Photo by Denise Stanley of a tadpole, in which we can see both the keratinous “teeth”, and the spiral-shaped intestine.

After metamorphosis, tadpoles will reabsorb their gills and tail, their digestive system will shorten, and will develop limbs and lungs, becoming small amphibians prepared for a life on land.

Recently metamorphosed spiny toad (Bufo spinosus) by David López.

As we have seen, the metamorphosis process varies greatly among the different species of each order. This process results in the fact that that most lissamphibians spend a part of their lives in water and the other on land, a representative fact of the transition of the first tetrapods from the aquatic to the terrestrial medium. Also, the great diversity of ecological niches occupied by both the adults and the larvae of the different species and the wide array of environmental factors that affect the metamorphosis process, make lissamphibians great bioindicators of an ecosystem’s health.

REFERENCES

The following sources have been consulted during the elaboration of this entry:

• Halliday & Adler (2007). La gran enciclopedia de los Anfibios y Reptiles. Editorial Libsa.
• Masó & Pijoan (2011). Anfibios y Reptiles de la Península Ibérica, Baleares y Canarias. Ediciones Omega.
• Brown & Cai (2007). Amphibian metamorphosis. Developmental Biology. Vol. 306. Pp: 20-33.
• Your Article Library. Process of Metamorphosis in Amphibians and it’s Hormonal Control.
• Metamorfosis de anfibios.
• Cover image by Brian Gratwicke.